The effects of volatile aromatic anesthetics on voltage-gated Na+ channels expressed in Xenopus oocytes.
BACKGROUND
Many inhaled anesthetics inhibit voltage-gated sodium channels at clinically relevant concentrations, and suppression of neurotransmitter release by these anesthetics results, at least partly, from decreased presynaptic sodium channel activity. Volatile aromatic anesthetics can inhibit N-methyl-D-aspartate (NMDA) receptor function and enhance gamma-amino butyric acid A receptor function, but these effects depend strongly on the chemical properties of the aromatic compounds. In the present study we tested whether diverse aromatic anesthetics consistently inhibit sodium channel function.


METHODS
We studied the effect of eight aromatic anesthetics on Na(v)1.2 sodium channels with beta(1) subunits, using whole-cell, two-electrode voltage-clamp techniques in Xenopus oocytes.


RESULTS
All aromatic anesthetics inhibited I(Na) (sodium currents) at a holding potential which produce half-maximal current (V(1/2)) (partial depolarization); inhibition was modest with 1,3,5-trifluorobenzene (8% +/- 2%), pentafluorobenzene (13% +/- 2%), and hexafluorobenzene (13% +/- 2%), but greater with benzene (37% +/- 2%), fluorobenzene (39% +/- 2%), 1,2-difluorobenzene (48% +/- 2%), 1,4-difluorobenzene (31 +/- 3%), and 1,2,4-trifluorobenzene (33% +/- 1%). Such dichotomous effects were noted by others for NMDA and gamma-aminobutyric acid A receptors. Parallel, but much smaller inhibition, was found for I(Na) at a holding potential which produced near maximal current (-90 mV) (V(H-90)), and hexafluorobenzene caused small (6% +/- 1%) enhancement of this current. These changes in sodium channel function were correlated with effectiveness for inhibiting NMDA receptors, with lipid solubility of the compounds, with molecular volume, and with cation-pi interactions.


CONCLUSIONS
Aromatic compounds vary in their actions on the kinetics of sodium channel gating and this may underlie their variable inhibition. The range of inhibition produced by minimum alveolar anesthetic concentration concentrations of inhaled anesthetics indicates that sodium channel inhibition may underlie the action of some of these anesthetics, but not others.
Horishita
Takafumi
T
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, 1 University Station A4800, Austin, TX 78712, USA.
Eger
Edmond I
EI
Harris
R Adron
RA
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001554:Benzene / Q000494:pharmacology; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology; D005466:Fluorocarbons / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014981:Xenopus
D000777:Anesthetics; D005464:Fluorobenzenes; D005466:Fluorocarbons; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D015222:Sodium Channels; C081153:1,2-difluorobenzene; C003005:hexafluorobenzene; D001554:Benzene